Project Summary Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence of circulating autoantibodies to nucleic acids and to proteins with which they associate, termed anti-nuclear antibodies (ANA). Immune complexes containing ANA and self-antigen from dying cells are pathological in SLE due to immune complex deposition in organs, and they also promote a feed forward loop in SLE by enhancing autoimmune responses in leukocytes that can endocytose these complexes. ANA immune complexes facilitate nucleic acid entry to the endosome via receptors binding the Fc portion of antibodies, where the endosomal- resident Toll-like receptors (TLRs) can promote cytokine production upon binding nucleic acids. Importantly, most studies have focused on IgG isotype ANA immune complex uptake and function despite the fact that SLE patients often have ANAs of multiple isotypes, including IgE and IgA. Plasmacytoid dendritic cells (pDCs) are one leukocyte that internalizes ANA ICs implicated in SLE pathogenesis. pDCs use endosomal TLR7 and TLR9 to respond to nucleic acids, resulting in the secretion of type I IFNs. These cytokines have pleiotropic effects on the immune response, all of which promote immune activation in SLE. pDCs express the IgG binding Fc receptor Fc?RII (CD32) through which they internalize IgG-containing ANA IC. Recently, pDC have been shown to express Fc?RI and internalize IgE-containing ANA IC leading to pDC IFN? production. However, IgE represents only ~0.01% of total serum antibodies. In contrast, IgA makes up ~15% of serum antibodies and IgA ANA have been identified in ~1/2 of SLE patients, yet the function of IgA in ANA IC has not been studied. Additionally, the presence of the human-specific IgA Fc receptor Fc?RI (CD89) has not been described on pDC. Here, we show novel preliminary data that human pDC express the IgA FcR Fc?RI (CD89), and that IgA in SLE serum is a critical component of IC-mediated pDC IFN? secretion. We propose to 1) Determine the role of IgA autoantibodies in anti-smRNP immune complex activation, and 2) Test the hypothesis that pDC from SLE patients have increased responses to IgA-containing immune complexes. Experiments in this proposal will use human samples from healthy control subjects and lupus patients available through the Benaroya Research Institute Immune Mediated Disease Registry and Repository.